The West Nile virus has surpassed all expectations spreading to 34 states and the District of Columbia since it was first detected in the United States in 1999. Having already been detected as far south as Texas and Florida, the virus continues to move westward. Experts believe it will infect California as early as next year. In addition to West Nile's obvious health threats, it is also a B class agent on the CDC's list of potential bioterrorist threat agents. These facts make the development of an anti-viral agent effective against West Nile a high priority. Previous studies have provided a proof-of-principle that a small disulfide-rich miniprotein can be developed that will block the infection of cells by the tick-borne Langat (Lgt) virus, a naturally attenuated virus that is a model for the pathogenic members of the tick-borne encephalitis (TBE) serogroup of the Flavivirus genus. The miniprotein termed MP-100 binds to domain III of the Langat envelope protein (LgtED3) and competes for cell receptor binding. The miniprotein MP-100 was shown to block infection of Vero and LLC-MK2 monkey kidney cell cultures by tick-borne Lgt and Powassan (POW) viruses. Further studies indicated significant antiviral activity in a mouse animal model. The goal of this Phase I SBIR is to provide a proof-of-principle that a miniprotein can be developed that binds tightly to West Nile virus E protein using RedStorm Scientific's proprietary Fyrestar TM drug design software platform. In a subsequent Phase II study the effectiveness of the resulting miniproteins against the mosquito-borne West Nile virus will be assessed. Binding and structural studies will be carried out against the West Nile envelope protein Domain III (WN-ED3). The structure of the complex will serve as a basis for the optimization of the miniprotein by the Fyrestar TM platform.